We have recently demonstrated that lncRNAs robustly regulate systemic lipid and glucose metabolism and their dysregulation could contribute to the pathogenesis of metabolic disease in mice (Li et al, Cell Metabolism, 2015, Ruan et al, Cell Reports, 2016 and Yang et al, Cell Metabolism, 2016). If lncRNAs play a similar role in human, understanding their functions could provide important insights into human metabolic physiology and open up novel therapeutic strategies. However, lncRNAs are much less conserved among species and it is estimated that majority (81%) of human lncRNAs are either primate- or human-specific (Nature 2014 Jan 30; 505) and their physiological function cannot be adequately studied in animal models. To develop a system to study the physiological role of human lncRNAs in energy metabolism, we have successfully produced liver-specific humanized mice in which over 90% mouse hepatocytes are replaced by engrafted human hepatocytes. We have used these mice to perform several genomewide screens and identified hundreds of human-specific and liver-enriched lncRNAs that are implicated in metabolic regulation. As a proof of principle, knockdown of selected lncRNAs systemically alter the expression of metabolic genes in the humanized livers. We are currently investigating the molecular mechanism by which these lncRNAs regulate metabolic circuitry and their significance in the maintenance of hepatic and systemic metabolic homeostasis.